Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. OBJECTIVE: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). METHODS: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). RESULTS: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. CONCLUSIONS: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer.

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Surgical Resection Alone is Associated With Higher Long-Term Survival Than Multiagent Chemotherapy Alone for Patients With Localized Biliary Tract Cancers.

INTRODUCTION: We compared long-term survival of patients with localized biliary tract cancers (BTCs) treated with either surgical resection or multiagent chemotherapy. METHODS: Patients with localized BTC [gallbladder adenocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma] were identified within the National Cancer Database (2010-2017). Piecewise-constant hazard modeling was used to estimate hazard ratios (HRs) at prespecified intervals: 0-30 d, 31-60 d, 61-90 d, and >90 d post-treatment. RESULTS: A total of 5988 patients with localized BTC were identified: 2697 (45.0%) received multiagent chemotherapy and 3291 (55.0%) underwent surgical resection. Patients with gallbladder adenocarcinoma or extrahepatic cholangiocarcinoma who were treated with surgical resection had an associated decline in overall survival (OS) as compared to those treated with multiagent chemotherapy within 0-30 d of treatment initiation (gallbladder adenocarcinoma [adjusted HR = 3.94, 95% confidence interval [CI]: 1.77-8.80]; extrahepatic cholangiocarcinoma [adjusted HR = 4.88, 95% CI: 2.76-8.61]). However, there was an associated improvement in OS for patients treated with surgical resection after 90 d from treatment initiation (gallbladder adenocarcinoma [adjusted HR = 0.36, 95% CI: 0.28-0.46]; extrahepatic cholangiocarcinoma [adjusted HR = 0.27, 95% CI: 0.24-0.32]). Among patients with intrahepatic cholangiocarcinoma, those who underwent surgical resection had an associated improvement in OS at 31-60 d (adjusted HR = 0.63, 95% CI: 0.40-0.99) and a further associated increase in OS at 61-90 d (adjusted HR = 0.34, 95% CI: 0.21-0.54) and after 90 d (HR = 0.23, 95% CI: 0.21-0.27) of treatment initiation. CONCLUSIONS: For patients with localized BTC, surgical resection alone is associated with improved long-term survival outcomes compared to multiagent chemotherapy alone.

Differences in the surgical management of early-stage hepatocellular carcinoma at minority versus non-minority-serving hospitals.

BACKGROUND: We examined differences in surgical intervention at minority-serving hospitals versus non-minority-serving hospitals among patients with early-stage hepatocellular carcinoma. We also investigated associations between surgical management and overall survival, stratified by minority-serving hospital status. METHODS: Patients with early-stage hepatocellular carcinoma, defined as cT1, were identified within the National Cancer Database (2004-2018). The primary outcome was surgical intervention (resection, ablation, or transplantation). The proportion of minority (non-Hispanic Black or Hispanic) patients treated at each facility was determined, and hospitals in the top decile were considered minority-serving hospitals. RESULTS: A total of 46,703 patients with early-stage hepatocellular carcinoma were identified, of whom 4,214 (9.0%) were treated at minority-serving hospitals. Patients treated at minority-serving hospitals were less likely to undergo surgical intervention than patients treated at non-minority-serving hospitals (odds ratio = 0.87, 95% confidence interval: 0.81-0.94). Minority patients treated at non-minority-serving hospitals were less likely to undergo surgical intervention than White patients (odds ratio = 0.86, 95% confidence interval: 0.82-0.90) and had a further associated decrease in the likelihood of surgical intervention when treated at minority-serving hospitals (odds ratio = 0.81, 95% confidence interval: 0.69-0.94). Regardless of minority-serving hospital status, surgery was associated with improved overall survival. There were no clinically meaningful differences in overall survival between White and minority patients who underwent surgery either at minority-serving hospitals or non-minority-serving hospitals. CONCLUSIONS: Patients with early-stage hepatocellular carcinoma had an associated decrease in the likelihood of surgical intervention when treated at minority-serving hospitals. Minority patients treated at minority-serving hospitals had an associated decrease in the likelihood of surgery, but to a lesser extent when treated at non-minority-serving hospitals. Surgery was associated with improved overall survival regardless of minority or minority-serving hospital status.

Disparities in guideline-compliant care for patients with pancreatic ductal adenocarcinoma at minority-versus non-minority-serving hospitals.

BACKGROUND: We examined disparities in guideline-compliant care at minority-serving hospitals (MSH) versus non-MSH among patients with localized or metastatic pancreatic adenocarcinoma (PDAC). METHODS: Patients with PDAC were identified within the National Cancer Database (2004-2018). Guideline-compliant care was defined as surgery + chemotherapy ± radiation therapy for localized and chemotherapy for metastatic disease. Facilities in the top decile of minority patients treated were considered MSH. RESULTS: A total of 190,950 patients were identified and most (59.6%) had metastatic disease. Overall, 6.4% of patients with localized and 8.2% of patients with metastatic disease were treated at MSH. Patients treated at MSH were less likely to receive guideline-compliant care (localized: OR = 0.78, 95% CI: 0.67-0.91; metastatic: OR = 0.77, 95% CI: 0.67-0.88). Minority patients were less likely to receive guideline-compliant care at non-MSH (localized: OR = 0.71, 95% CI: 0.67-0.75; metastatic: OR = 0.85, 95% CI: 0.82-0.89) or MSH (localized: OR = 0.85, 95% CI: 0.74-0.98; metastatic: OR = 0.91, 95% CI: 0.82-0.99). Patients treated at non-MSH or MSH who received guideline-compliant care were more likely to have higher OS regardless of stage or race. CONCLUSIONS: MSH patients were less likely to receive guideline-compliant care and minority patients were less likely to receive guideline-compliant care regardless of MSH status. Guideline-compliant care was associated with improved OS.

Hypercalcemia of malignancy caused by parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumors (PTHrP-PNETs): Case Report.

Parathyroid hormone-related protein (PTHrP) secretion is occasionally detected in various solid tumors such as renal cell carcinoma and lung cancers. It is considered quite rare for neuroendocrine tumors with only few published case reports. We reviewed the current literature and summarized a case report of a patient with metastatic pancreatic neuroendocrine tumor (PNET) presenting with hypercalcemia due to elevation of PTHrP. The patient had histological confirmation of well-differentiated PNET and developed hypercalcemia years after his initial diagnosis. In our case report, evaluation showed intact parathyroid hormone (PTH) in the setting of concomitant elevation of PTHrP. The patient's hypercalcemia and PTHrP levels were improved by using a long-acting somatostatin analogue. In addition, we reviewed the current literature regarding the optimal management of malignant hypercalcemia due to PTHrP-producing PNETs.

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. TRIAL REGISTRATION NUMBER: NCT02376699.

The predictive impact of dual somatostatin receptor/fluorodeoxyglucose (FDG) positron emission tomography (PET) in metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs): review of literature and a single institution experience.

Treatment with radiolabelled somatostatin analogs, a form of peptide receptor radionuclide therapy (PRRT), has changed the management of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who have suboptimal benefit and rapidly progress on PRRT, indicating that accurate prognostic and predictive markers are urgently needed. Currently, most of the literature concentrate on the prognostic impact of the dual positron emission tomography (PET) scan with very few information regarding the predictive value. We report a case series and review the literature to summarizes the predictive value of combined somatostatin receptor (SSTR) and fluorodeoxyglucose (FDG) PET in metastatic GEP-NETs. We conducted a review of the literature for data published from 2010 to 2021 in MEDLINE, Embase, the National Institutes of Health trial registry, Cochrane CENTRAL, and published proceedings from major gastrointestinal and neuroendocrine cancer meetings. Our main criteria included all published prospective and retrospective data in which the predictive value of dual PET scans using SSTR and FDG was correlated with PRRT response in patients with metastatic GEP-NETs. We summarized clinical outcomes including progression-free survival (PFS), overall survival (OS), and post-therapy complications associated with PRRT according to FDG avidity. We excluded studies that did not include FDG PET scan, GEP patients, studies with no clear predictive value of the FDG PET scan, and studies that did not report a direct correlation between FDG avidity and primary outcome. Additionally, we summarized our institutional experience in eight patients who progressed during or within the first year of PRRT treatment. Our search identified 1306 articles; most of them showed only the prognostic value of Integrated SSTR/FDG PET imaging biomarker in GEP-NETs. Only three studies (n=75 patients) met our inclusion criteria and retrospectively investigated the predictive value of dual SSTR and FDG imaging in subjects being considered for PRRT. The results confirmed that FDG avidity correlates with advanced NET grades. Lesions that are both SSTR and FDG avid had early disease progression. In one study, at multivariate analysis, FDG PET results were independently predictive of lower PFS for PRRT. In our case series, there were eight patients with metastatic well-differentiated GEP-NETs (grades 2 and 3) who progressed within one year of PRRT. Seven of them had positive FDG PET scan at the time of progression. In conclusion, Dual SSTR/FDG PET imaging has a potential predictive impact for PRRT in GEP-NETs. It permits the capturing of the disease complexity and aggressiveness, which correlates with PRRT response. Therefore, prospective future trials should validate the predictive value of dual SSTRs/FDG PET for better PRRT stratification.

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study.

BACKGROUND: HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. METHODS: MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. FINDINGS: Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. INTERPRETATION: Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer. FUNDING: Seagen and Merck & Co.

Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer.

OBJECTIVE: To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS: Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS: Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (ß = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS: Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.

Trends and disparities in the utilization of systemic chemotherapy in patients with metastatic hepato-pancreato-biliary cancers.

BACKGROUND: We described trends and disparities in utilization of systemic chemotherapy in metastatic hepato-pancreato-biliary (HPB) cancers. METHODS: We queried the National Cancer Database for metastatic HPB cancers [hepatocellular carcinoma (HCC), biliary tract cancers (BTC), pancreatic adenocarcinoma (PDAC)]. We used multivariable analysis to examine the factors associated with utilization of systemic chemotherapy. We utilized marginal structural logistic models to estimate the effect of health insurance, facility type, or facility volume on utilization of systemic chemotherapy. RESULTS: We identified 162,283 patients with metastatic HPB cancers: 23,923 (14.7%) had HCC, 26,766 (16.5%) had BTC, and 111,594 (68.8%) had PDAC. A total of 37.2% patients with HCC, 55.6% with BTC, and 56.4% with PDAC received chemotherapy. Age ≥70 years and Charlson-Deyo score ≥2 were associated with lower likelihood of receiving chemotherapy across all cancers. Patients with private health insurance had higher receipt of chemotherapy. Receiving treatment at academic facilities had no effect on the receipt of chemotherapy. Treatment of patients with HCC or PDAC at high-volume facilities resulted in higher receipt of chemotherapy. CONCLUSION: A significant proportion of patients with metastatic HPB cancers do not receive systemic chemotherapy. Several disparities in administration of chemotherapy for metastatic HPB cancers exist.

Average treatment effect of facility hepatopancreatobiliary malignancy case volume on survival of patients with nonoperatively managed hepatobiliary malignancies.

BACKGROUND: Surgical volume-outcome relationships have been described for a variety of procedures. There is scant literature on total institutional volume and outcomes in patients who are nonoperatively managed. We examined the average treatment effect of total hepatopancreatobiliary malignancy case volume on survival outcomes of patients with nonresected hepatobiliary malignancies. METHODS: We identified patients with hepatopancreatobiliary malignancies [pancreatic adenocarcinoma, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers] within the National Cancer Database (2004-2018). We determined percentile thresholds based on the total annual hepatopancreatobiliary malignancy case volume. We then identified nonoperatively managed patients with hepatocellular carcinoma or biliary tract cancers. We used inverse probability-weighted Cox regression to estimate the effect of facility volume on overall survival. RESULTS: We identified 710,988 patients with hepatopancreatobiliary malignancies. Total annual hepatopancreatobiliary malignancy case volume of 32, 71, and 177 cases/year corresponded to the 25th, 50th, and 75th percentiles. A total of 96,420 with hepatocellular carcinoma and 52,627 patients with biliary tract cancers were managed nonoperatively. In patients with hepatocellular carcinoma or biliary tract cancer, treatment at ≥25th, ≥50th, and ≥75th percentile facilities was associated with improved median, 1-, 2-, and 3-year overall survival compared with treatment at lower-percentile facilities. On inverse probability-weighted Cox analysis, treatment at higher-percentile facilities resulted in a lower hazard of death. Consistent findings were observed in patients with early or intermediate/advanced hepatocellular carcinoma or metastatic biliary tract cancers. CONCLUSION: Patients with nonoperatively managed hepatocellular carcinoma or biliary tract cancer who receive treatment at higher-volume facilities have improved survival outcomes. These data suggest regionalization of care for patients with hepatocellular carcinoma or biliary tract cancer to high-volume centers may improve survival.

Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer.

BACKGROUND: KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C-mutated pancreatic cancer are unknown. METHODS: We conducted a single-group, phase 1-2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C-mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed. RESULTS: The pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation. CONCLUSIONS: Sotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C-mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.).

Caregiver Burden in Distance Caregivers of Patients with Cancer.

Distance caregivers (DCGs), those who live more than an hour away from the care recipient, often play a significant role in patients' care. While much is known about the experience and outcomes of local family caregivers of cancer patients, little is known about the experience and outcomes of distance caregiving upon DCGs. The purpose of this study was to identify the relationships among stressors (patient cancer stage, anxiety, and depression), mediators (DCG emotional support and self-efficacy), and burden in DCGs' of patients with cancer. This study was a descriptive cross-sectional study and involved a secondary data analysis from a randomized clinical trial. The study sample consisted of 314 cancer patient-DCG dyads. The results of this study were: (1) 26.1% of DCGs reported elevated levels of burden; (2) significant negative relationships were found between mediators (DCG emotional support and self-efficacy) and DCG burden; and (3) significant positive relationships were found between patient anxiety, depression, and DCG burden. The prevalence of burden in DCGs, and its related factors, were similar to those of local caregivers of cancer patients, which suggests that interventions to reduce burden in local caregivers could be effective for DCGs as well.

Thymoquinone Plus Immunotherapy in Extra-Pulmonary Neuroendocrine Carcinoma: Case Series for a Novel Combination.

BACKGROUND: Neuroendocrine neoplasms (NENs) are a heterogeneous group of cancers that had a significant increase in annual incidence in the last decade. They can be divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Poorly differentiated NECs are aggressive forms of cancers with limited therapeutic options. The first line treatment of metastatic poorly differentiated NECs is similar to small cell lung cancer, with cytotoxic chemotherapy (etoposide plus platinum). Patients who progress have limited therapeutic options and poor overall survival, calling for other novel agents to combat this deadly disease. Therefore, in this article, we summarized the effects of a novel component, Thymoquinone (TQ, C10H12O2), which is the main bioactive component of the black seed (Nigella sativa, Ranunculaceae family), plus immunotherapy in case series of patients with refractory metastatic extra-pulmonary NEC (EP-NEC) and one case of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). METHODS: We report the effect of TQ plus dual immune checkpoint inhibitors (nivolumab plus ipilimumab) in four patients with poorly differentiated gastrointestinal Ep-NEC and MiNEN who progressed on cytotoxic chemotherapy. RESULTS: This is the first case series to report the clinical activity of TQ plus dual immune checkpoint inhibitors (nivolumab plus ipilimumab) in patients with refractory metastatic EP-NEC. The four patients showed benefits with the combined regimen TQ plus dual ICPIs with durable response and exceeded the two years of progression-free survival. None of the four patients experienced significant toxicity, and all of them showed improvement in quality of life. CONCLUSION: The reported clinical courses suggest that combined TQ plus ICPIs is a potential promising regimen for refractory EP-NEC and MiNEN that deserves further prospective investigation.

Average treatment effect of facility hepatopancreatobiliary cancer volume on survival of non-resected pancreatic adenocarcinoma.

BACKGROUND: To examine the average treatment effect of hepato-pancreato-biliary (HPB) cancer volume on survival outcomes of patients with non-resected pancreatic adenocarcinoma (PDAC). METHODS: We queried the National Cancer Database (2004-2018) for patients with HPB malignancies (PDAC, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers). We determined the 25th, 50th, and 75th percentiles based on the total annual HPB volume. We then identified patients with non-resected PDAC. We utilized inverse probability (IP)-weighted Cox regression to estimate the effect of facility volume on overall survival (OS). RESULTS: We identified 710,988 patients with HPB malignancies. The 25th, 50th, and 75th percentiles of total annual HPB volume were 32, 71, and 177 cases/year, respectively. We included a total of 196,150 patients with non-resected PDAC. Patients treated at ≥25th, ≥50th, and ≥75th percentile facilities had improved median OS compared to those treated at facilities below these thresholds (5.8 vs. 4.2months, 6.5 vs. 4.5months, 7.5 vs. 4.8months, respectively; p < 0.001 for all). Treatment at facilities ≥25th, ≥50th, and ≥75th percentile resulted in lower hazards of death than treatment at lower-percentile facilities (HR: 0.87, 95% CI: 0.84-0.90; HR: 0.87, 95% CI: 0.83-0.91; HR: 0.85, 95% CI: 0.79-0.91, respectively). CONCLUSION: Our data suggest that consolidation of care of patients with PDAC to high-volume centers may be beneficial even in the nonoperative setting.

Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non-small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial.

BACKGROUND: Dostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non-small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284). MATERIALS AND METHODS: Here, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety. RESULTS: As of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients. CONCLUSION: Dostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile.

The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

Assessing the Role of Operative Intervention in Elderly Patients With Nonfunctional Pancreatic Neuroendocrine Neoplasms.

OBJECTIVES: Resection of locoregional pancreatic neuroendocrine neoplasms (PanNENs) is typically recommended, but there is a paucity of data on the management of elderly patients. METHODS: The National Cancer Database (2004-2016) was queried for patients 80 years or older with localized PanNENs. Patients were grouped as nonoperative or operative management. Postoperative outcomes and survival were compared. RESULTS: In total, 591 patients were included: 202 underwent resection, and 389 did not. Increasing age and pancreatic head tumors were associated with lower likelihood of resection. The overall 90-day mortality rate was 6.4%, which was higher for pancreatoduodenectomy than distal pancreatectomy (13.6% vs 5.1%, respectively). Operatively managed patients had longer median survival (80.8 vs 45.0 months, P < 0.001), and this association was independent of tumor location. On multivariable Cox regression, resection remained associated with longer survival (hazard ratio, 0.69; 95% confidence interval, 0.50-0.95). Among operatively managed patients, age and tumor location were not associated with survival; however, greater comorbidity and high-risk tumor-specific features were associated with worse survival. CONCLUSIONS: Resection of nonfunctional PanNENs in elderly patients is associated with improved survival compared with nonoperative management. Resection could be considered in appropriate operative candidates, regardless of tumor location, but the perioperative mortality rate must be considered.